This application is the national phase under 35 U.S.C. xc2xa7 371 of PCT International Application No. PCT/JP98/03096 which has an International filing date of Jul. 10, 1998, which designated the United States of America.
The present invention relates to a stable pharmaceutical composition including 4,5-epoxy-morphinan derivative or pharmacologically acceptable acid-addition salts thereof. More particularly, the present invention relates to a stable pharmaceutical composition including 4,5-epoxy-morphinan derivative which includes 4,5-epoxy-morphinan derivative as an effective component and includes a water soluble antioxidant, a fat soluble antioxidant, a synergist, a sugar, or a surfactant, and also relates to a method for stabilizing the pharmaceutical composition.
Morphine has a significant analgesic effect and is indicated for conditions such as postoperative pain and cancer pain. However, the drug has severe adverse reactions such as being addictive and causing respiratory depression and constipation, which induces clinical problems. Therefore, morphine is an analgesic which demands meticulous care.
Recently, it has become clear that opiate receptors may be classified into three types, that is, xcexc, xcex4, and xcexa receptor, which function as central analgesic receptors. In addition, an opiate "sgr" receptor has also been elucidated which affects mental function.
The severe adverse reactions accompanied by administration of morphine are specific to the xcexc receptor agonist and to the "sgr" receptor agonist. The xcex4 receptor agonist and the xcexa receptor agonist seem not to show the above-mentioned adverse reactions.
A 4,5-epoxy-morphinan derivative does not induce the severe adverse reactions accompanied by the administration of morphine. In addition, the 4,5-epoxy-morphinan derivative is agonistic to the xcexa receptor or to the xcex4 receptor, and shows significant analgesic and diuretic activities. Furthermore, the 4,5-epoxy-morphinan derivative does not show cross-tolerance with morphine or the like, and does not show an affinity for the "sgr" receptor. Therefore, the 4,5-epoxy-morphinan derivative is a promising analgesic and a promising diuretic (WO93/15081).
However, the 4,5-epoxy-morphinan derivatives are chemically unstable to heat, light, and oxygen. Thus, means such as low-temperature storage, light protection, and displacement by an inert gas are necessary to store them.
Therefore, it is significantly useful that a stable pharmaceutical preparation including these 4,5-epoxy-morphinan derivatives is prepared.
With respect to a conventional stabilizing method for morphine, that is, a morphinan derivative, for example, in Japanese Unexamined Patent Publication No. 2-160719, an attempt to improve stability of a pharmaceutical preparation is made by adding a basic component to morphine. In addition, a stabilized pharmaceutical composition (DE29719704) or the like is known in which an antioxidant such as sodium thiosulfate or tocopherol is accompanied by naloxone. However, with respect to a 4,5-epoxy-morphinan derivative, a stabilized composition and a method of stabilization therefore has not been determined heretofore.
An object of the present invention is to provide a stable pharmaceutical composition including a 4,5-epoxy-morphinan derivative and also to provide a method for stabilizing it.
The present invention relates to a pharmaceutical composition including a 4,5-epoxy-morphinan derivative and at least one substance selected from the group consisting of the following materials (1), (2), (3), (4) and (5).
(1) A water soluble antioxidant selected from the group consisting of sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, Rongalite, L-ascorbic acid, erysorbic acid, sodium thiosulfate, sodium thiomalate, cysteine, thioglycerol, and hydroxyquinoline sulfate.
(2) A fat soluble antioxidant selected from the group consisting of propyl gallate, butyl hydroxytoluene, butyl hydroxyanisole, tocopherol, ascorbyl palmitate, ascorbyl stearate, nordihydroguaiaretic acid, and mercaptobenzimidazole.
(3) A synergist selected from the group consisting of EDTA, salts thereof, citric acid, salts thereof, and lecithin.
(4) A sugar selected from the group consisting of D-mannitol, D-sorbitol, xylitol, glucose, and fructose.
(5) A surfactant selected from the group consisting of sorbitan sesquioleate, sorbitan laurate, sorbitan palmitate, glyceryl myristate, polyoxyethylene nonylphenyl ether, and polyoxyethylene lauryl ether.
The present invention relates to stable pharmaceutical compositions including a 4,5-epoxy-morphinan derivative and at least one component selected from the group consisting of a water soluble antioxidant, a fat soluble antioxidant, a synergist, a sugar, and a surfactant.
A 4,5-epoxy-morphinan derivative in accordance with the present invention can be prepared by the method disclosed in WO93/15081 and is a compound represented by the general formula (I) or pharmacologically acceptable acid-addition salts thereof: 
wherein - - - is a double bond or a single bond; R1 is an alkyl group having from 1 to 5 carbon atoms, a cycloalkylalkyl group having from 4 to 7 carbon atoms, a cycloalkenylalkyl group having from 5 to 7 carbon atoms, an aryl group having from 6 to 12 carbon atoms, an aralkyl group having from 7 to 13 carbon atoms, an alkenyl group having from 4 to 7 carbon atoms, an allyl group, a furan-2-ylalkyl group having from 1 to 5 carbon atoms, or a thiophene-2-ylalkyl group having from 1 to 5 carbon atoms; R2 is a hydrogen atom, a hydroxy group, a nitro group, an alkanoyloxy group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, an alkyl group having from 1 to 5 carbon atoms, or xe2x80x94NR7R8; R7 is a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; R8 is a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, or xe2x80x94C(xe2x95x90O)R9; R9 is a hydrogen atom, a phenyl group, or an alkyl group having from 1 to 5 carbon atoms; R3 is a hydrogen atom, a hydroxy group, an alkanoyloxy group having from 1 to 5 carbon atoms, or an alkoxy group having from 1 to 5 carbon atoms; A is xe2x80x94N(R4)C(xe2x95x90X)xe2x80x94, xe2x80x94N(R4)C(xe2x95x90X)Yxe2x80x94, xe2x80x94N(R4)xe2x80x94, or xe2x80x94N(R4)SO2xe2x80x94 (wherein X and Y are, independently of one another, NR4, S, or O; and R4 is a hydrogen atom, a straight-chain or branched-chain alkyl group having from 1 to 5 carbon atoms, or an aryl group having from 6 to 12 carbon atoms; and R4 may be identical or different in the formula); B is a valence bond, a straight-chain or branched-chain alkylene group having from 1 to 14 carbon atoms (wherein the alkylene group may be substituted with one or more substituents selected from the group consisting of an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group and a phenoxy group, and wherein one to three methylene groups of the alkylene group may be replaced with carbonyl groups), a straight-chain or branched-chain acyclic unsaturated hydrocarbon containing from one to three double bonds and/or triple bonds and having from 2 to 14 carbon atoms (wherein the acyclic unsaturated hydrocarbon may be substituted with one or more substituents selected from the group consisting of an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group and a phenoxy group, and wherein one to three methylene groups of the acyclic unsaturated hydrocarbon may be replaced with carbonyl groups), or a straight-chain or branched-chain saturated or unsaturated hydrocarbon containing from one to five thioether, ether and/or amino bonds and having from 1 to 14 carbon atoms (wherein no hetero atoms are bonded directly to A, and one to three methylene groups of the hydrocarbon may be replaced with carbonyl groups); and R5 is a hydrogen atom or an organic group having a basic skeleton selected from the group consisting of following formulas: 
wherein the organic group may have at least one substituent selected from the group consisting of an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitro group, a cyano group, an isothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group, and a methylenedioxy group; R6 is a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms or an alkanoyl group having from 1 to 5 carbon atoms.
In the general formula (I), R1 is preferably a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group, a cyclopropylmethyl group, an allyl group, a benzyl group, or a phenethyl group, and more preferably a cyclopropylmethyl group or an allyl group.
R2 and R3 are preferably a hydrogen atom, a hydroxy group, an acetoxy group, or a methoxy group, independently.
A is preferably xe2x80x94N (R4)C(xe2x95x90O)xe2x80x94, xe2x80x94N(R4)C(xe2x95x90O)Oxe2x80x94, xe2x80x94N(R4)xe2x80x94, or xe2x80x94N(R4)SO2xe2x80x94 (wherein R4 is a hydrogen atom, or a straight-chain or branched-chain alkyl group having from 1 to 5 carbon atoms). Among them A is more preferably xe2x80x94N(R4)C(xe2x95x90O)xe2x80x94 or xe2x80x94N(R4)C(xe2x95x90O)Oxe2x80x94 (wherein R4 is a hydrogen atom, or a straight-chain or branched-chain alkyl group having from 1 to 5 carbon atoms).
B is preferably a straight-chain alkylene group having from 1 to 3 carbon atoms, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2Oxe2x80x94 or xe2x80x94CH2Sxe2x80x94. Among them, B is more preferably a straight-chain alkylene group having from 1 to 3 carbon atoms, xe2x80x94CHxe2x95x90CHxe2x80x94, or xe2x80x94Cxe2x89xa1Cxe2x80x94.
R5 is preferably a hydrogen atom or an organic group having a basic skeleton selected from the group consisting of the following basic formulas: 
wherein the organic group may be substituted with one or more substituents selected from the group consisting of an alkyl group having from 1 to 5 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, an alkanoyloxy group having from 1 to 5 carbon atoms, a hydroxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an amino group, a nitro group, a cyano group, an isothiocyanate group, a trifluoromethyl group, a trifluoromethoxy group, and a methylenedioxy group.
R6 is preferably a hydrogen atom.
17-(cyclopropyl methyl)-3,14xcex2-dihydroxy-4,5xcex1-epoxy-6xcex2-[N-methyl-trans-3-(3-furyl)acrylamide]morphinan hydrochloride (hereinafter referred to as xe2x80x9cCompound 1xe2x80x9d) and 17-(cyclopropyl methyl)-3,14xcex2-dihydroxy-4,5xcex1-epoxy-6xcex2-[N-methyl-3-(4-trifluoromethylphenyl)propiolamide]morphinan hydrochloride (hereinafter referred to as xe2x80x9cCompound 2xe2x80x9d) are particularly preferred. 
The pharmacologically acceptable acid-addition salts thereof are inorganic acid salts, such as chlorides, sulfates, nitrates, hydrobromides, hydroiodides, and phosphates; organic carboxylates, such as acetates, lactates, citrates, oxalates, glutarates, malates, tartrates, fumarates, mandelates, maleates, benzoates, and phthalates; and organic sulfonates, such as methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and camphor-sulfonates. Among them, chlorides, hydrobromides, phosphates, tartrates, malates, and methanesulfonates are preferred, but of course the pharmacologically acceptable acid-addition salts thereof are not limited to these compounds.
With respect to a composition content of the 4,5-epoxy-morphinan derivative, that is, an effective component, any content may be available, even if the content of the effective component in a pharmaceutical composition is sufficient for a treatment. For example, the content may range from 0.01 to 10000 xcexcg/pharmaceutical composition. Ordinarily, the content preferably ranges from 0.1 to 1000 xcexcg/pharmaceutical composition.
In the present invention, sulfites, nitrites, ascorbic acids, thiol derivatives, hydroxyquinoline sulfate, or the like is used as a water soluble antioxidant. Phenolic compounds, fat soluble vitamins, ascorbic acid esters, fat soluble vitamins, nordihydroguaiaretic acid, mercaptobenzimidazole, or the like is used as a fat soluble antioxidant. EDTA, salts thereof, citric acid, salts thereof, lecithin, or the like is used as a synergist. The above-mentioned synergist shows a weak antioxidant effect by itself. However, the effect can be increased in combination with other antioxidants.
Specifically, a sulfite such as sodium sulfite, sodium hydrogensulfite, sodium pyrosulfite, or Rongalite, a nitrite such as sodium nitrite, a ascorbic acid such as L-ascorbic acid or erysorbic acid, and a thiol derivative such as sodium thiosulfate, sodium thiomalate, cysteine, thioglycerol, or hydroxyquinoline sulfate is used as a water soluble antioxidant. Among them, sodium thiosulfate is most preferable.
A phenolic compound such as propyl gallate, butyl hydroxytoluene, or butyl hydroxyanisole, a fat soluble vitamin such as tocopherol or a fat soluble vitamin such as ascorbyl palmitate, ascorbyl stearate, nordihydroguaiaretic acid, or mercaptobenzimidazole is used as a fat soluble antioxidant. Among them, propyl gallate, butyl hydroxytoluene or butyl hydroxyanisole is preferable.
For example, EDTA, salts thereof, citric acid, salts thereof, lecithin, or the like is used as a synergist. With respect to salts, sodium salts, calcium salts, potassium salts, or magnesium salts are preferable. Among them, EDTA or citric acid is more preferable.
At least one selected from the group consisting of above-described water soluble antioxidants, fat soluble antioxidants, and synergists is used as an antioxidant. In addition, at least one sugar or at least one surfactant can be mixed therein.
The content of the antioxidant ranges from 0.00001 to 10 percent by weight of the total pharmaceutical composition, preferably ranges from 0.001 to 10 percent by weight of the total pharmaceutical composition, and more preferably 0.001 to 1 percent by weight of the total pharmaceutical composition.
It is confirmed that the antioxidant is sufficiently effective when it is solved or dispersed in a solution, or when it is dispersed in a semisolid or in a solid. The antioxidant is effective for stabilization of all dosage forms such as syrups, powders, fine granules, granules, tablets, hard capsules, soft capsules, injections, freeze-drying dosage forms, ointments, tapes, lotions, nose drops, ophthalmic solutions, aerosols, suspensions, emulsions, plasters, and suppositories.
Specifically, a sugar used in the present invention, for example, is D-mannitol, D-sorbitol, xylitol, glucose, maltose, fructose, sucrose, or white soft sugar.
Preferably, D-mannitol, D-sorbitol, xylitol, glucose, or fructose is used alone or used in a mixture of at least two thereof. Furthermore, at least one of water soluble antioxidants, fat soluble antioxidants, synergists, and surfactants can be mixed therein.
The content of the sugar ranges from 0.01 to 20 percent by weight of the total pharmaceutical composition, preferably ranges from 0.1 to 20 percent by weight of the total pharmaceutical composition, and more preferably 1 to 20 percent by weight of the total pharmaceutical composition.
It is confirmed that addition of sugars is particularly useful for stabilization of injections. In addition, it has been shown that when a water soluble antioxidant, a fat soluble antioxidant, or a synergist as an antioxidant is added, a greater stabilization effect can be obtained. Among them, D-mannitol, D-sorbitol, xylitol, and glucose are useful for stabilization of the injections. With respect to the accompanying antioxidant, sodium thiosulfate, that is, a water soluble antioxidant and citric acid, that is, a synergist, are particularly preferable.
Specifically, a surfactant used in the present invention, for example, is sorbitan sesquioleate, sorbitan laurate, sorbitan palmitate, glyceryl myristate, polyoxyethylene nonylphenyl ether, and polyoxyethylene lauryl ether.
Preferably, glyceryl myristate or polyoxyethylene nonylphenyl ether is used alone or used as a mixture of at least two thereof. Furthermore, at least one of water soluble antioxidants, fat soluble antioxidants, synergists, and sugars can be mixed therein.
The content of the surfactant ranges from 0.0001 to 20 percent by weight of the total pharmaceutical composition, preferably ranges from 0.001 to 20 percent by weight of the total pharmaceutical composition, and more preferably 0.01 to 10 percent by weight of the total pharmaceutical composition.
It is confirmed that addition of the surfactant is particularly useful for stabilization of external preparations such as ointments, gels, tapes, lotions, nose drops, ophthalmic solutions, aerosols, and suppositories. In addition, it is shown that when a water soluble antioxidant, a fat soluble antioxidant, or a synergist as an antioxidant is added, a greater stabilization effect can be obtained. Among them, glyceryl myristate and polyoxyethylene nonylphenyl ether are useful for stabilization of the external preparations. With respect to the accompanying antioxidant, citric acid, that is, a synergist, is particularly preferable.
An available additive such as vehicles, binders, thickener, solubilizer, solvents, isotonizing agents, buffers, preservatives, or bases may be added to the pharmaceutical compositions in accordance with the present invention, if necessary.
The additives in the present invention are not particularly limited, even though they are pharmaceutically acceptable. Examples of a vehicle are lactose, white soft sugar, sucrose, sorbitol, microcrystalline cellulose, corn starch, gelatin, dextrans and the like. Examples of a binder are hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl pyrrolidone, methyl cellulose, and the like. Examples of a thickener are gum arabic, sodium hyaluronate, xanthan gum, and the like. Examples of a solvent are water, ethanol, propylene glycol, polyethylene glycol, Polysorbate 80, glycerin, soybean oil and the like. Examples of an isotonizing agent are sodium chloride, D-mannitol, xylitol, glucose and the like. Examples of a solubilizer are cyclodextrin and the like. Examples of a nonionic surfactant are polyoxyethylene hydrogenated castor oil, sorbitan sesquioleate, sorbitan laurate, sorbitan palmitate, glyceryl oleate, glyceryl myristate, polyoxyethylene lauryl ether, polyoxyethylene nonylphenyl ether, and the like. Examples of a buffer are tartaric acid, citric acid, maleic acid, phosphoric acid, succinic acid, lactic acid, acetic acid, sodium hydrogencarbonate, boric acid, sodium borate, magnesium oxide, magnesium hydroxide, and the like. Examples of a preservative are methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, benzalkonium chloride, and the like. Examples of a base are white petrolatum, Witepsol, Plastibase, liquid paraffin, and the like.
The pharmaceutical compositions in accordance with the present invention are not particularly limited, even though they have pharmaceutically acceptable dosage forms for administration. The pharmaceutical compositions in accordance with the present invention are available for all dosage forms such as syrups, powders, fine granules, granules, tablets, hard capsules, soft capsules, injections, freeze-drying dosage forms, ointments, gels, tapes, lotions, nose drops, ophthalmic solutions, aerosols, suspensions, emulsions, plasters, and suppositories.